Experimental Stroke Induces Chronic Gut Dysbiosis and Neuroinflammation in Male Mice

Brichacek, A. L.; Nwafor, D. C.; Benkovic, S. A.; Chakraborty, S.; Kenney, S. M.; Mace, M.; Jun, S.; Gambill, C. A.; Wang, W.; Hu, H.; Ren, X.; Povroznik, J. M.; Engler-Chiurazzi, E. B.; Primerano, D.; Denvir, J.; Percifield, R.; Infante, A.; Franko, J.; Schafer, R.; Gemoets, D. E.; Brown, C. M.

doi:10.1101/2020.04.29.069575

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bioRxiv · 10.1101/2020.04.29.069575

Experimental Stroke Induces Chronic Gut Dysbiosis and Neuroinflammation in Male Mice

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Abstract

Recent literature implicates gut epithelia mucosa and intestinal microbiota as important players in post-stroke morbidity and mortality. As most studies have focused on the acute effects of stroke on gut dysbiosis, our study objective was to measure chronic, longitudinal changes in the gut microbiota and intestinal pathology following ischemic stroke. We hypothesized that mice with experimental ischemic stroke would exhibit chronic gut dysbiosis and intestinal pathology up to 36 days post-stroke compared to sham controls. Male C57BL/6J mice were subjected to 60 minutes of transient middle cerebral artery occlusion (tMCAO) or sham surgery. To determine the long-term effects of tMCAO on gut dysbiosis, fecal boli were collected pre- and post-tMCAO on days 0, 3, 14, and 28. Bioinformatics analysis demonstrate significant differences in abundance among Firmicutes and Bacteroidetes taxa at the phylum, family, and species levels in tMCAO compared to sham mice that persisted up to one month post-stroke. The most persistent changes in post-stroke microbial abundance were a decrease in bacteria family S24-7 and significant increases in Ruminococcaceae. Overall, these changes resulted in a persistently increased Firmicutes:Bacteroidetes ratio in stroke animals. Intestinal histopathology showed evidence of chronic intestinal inflammation that included marked increases in immune cell infiltration with mild-moderate epithelial hyperplasia and villous blunting. Increased astrocyte and microglial activity were also detected one-month post-stroke. These results demonstrate that acute, post-stroke disruption of the gut-brain-microbiota axis progresses to chronic gut dysbiosis, intestinal inflammation, and chronic neuroinflammation. Clinical PerspectivesO_LIThe microbiota-gut-brain axis, recently implicated in several neurological disorders, remains largely unexplored at chronic time points post-tMCAO. C_LIO_LIOur results demonstrate chronic gut dysbiosis, prolonged behavioral deficits, and persistent cerebral and intestinal inflammation post-tMCAO in male C57BL/6J mice. C_LIO_LIThese results suggest that manipulation of microbiota may help reduce poor outcomes after stroke and lead to improved post-stroke functional recovery. C_LI

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Brichacek, A. L., Nwafor, D. C., Benkovic, S. A., Chakraborty, S., Kenney, S. M., Mace, M., Jun, S., Gambill, C. A., Wang, W., Hu, H., Ren, X., Povroznik, J. M., Engler-Chiurazzi, E. B., Primerano, D., Denvir, J., Percifield, R., Infante, A., Franko, J., Schafer, R., Gemoets, D. E., Brown, C. M.. 2020-05-01. Experimental Stroke Induces Chronic Gut Dysbiosis and Neuroinflammation in Male Mice. https://doi.org/10.1101/2020.04.29.069575

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